Contents A The cell B Tissue types C Nerve cell D Synthesis E Vulnerabilities F Plasmalemma G Unit membrane H Nucleus I Endoplasmic reticulum J Membrane vulnerabilities K Gut enterocyte L Macrophage M Cardiac muscle cell QuestionsA The cell is the unit of life able to direct the elaborate chemistry that keeps it alive, and coordinating its work with that of the trillions of other cells comprising a human being. By means of an active, constantly changing 'skin' - the cell membrane, plasmalemma or plasmamembrane, that demarcates and defines it - the cell specifies what materials and messages come in, and what signals, products, and wastes are sent out. Thus, the cell (L 2-1; Fig. 1) attends simultaneously to its three interest areas:
C We shall use the nerve cell to illustrate in detail what structures a cell has to have to function effectively.
a) First, it must have a shape, be attached to its surroundings, and have a nutrient pathway to it. The overwhelming majority of neurons are multipolar, extending out many branching and progressively narrowing processes from a cell body or soma, housing the driving structures of the cell, such as the nucleus (L Fig. 22-11). These branching extensions of the cell - dendrites - are sensitive to chemicals released by other neurons, and the electrical potentials thus provoked across the dendritic membranes combine with similarly induced potentials on the membrane of the cell body or soma. One region of the somatic membrane differs in that it narrows down into a single long extension of the cell membrane that is called the axon. The first part of the axon is the initial segment, and it and the immediately adjacent tapering region of the soma's membrane act as the trigger zone. This zone starts the action potential along the axon, if the dendritic and somatic electrical events reach a critical value in a set period: in Physiology time is of the essence.
b) The axon keeps its width, as it extends through the brain or spinal cord, or along a peripheral nerve. However, when it gets close to its target it often branches to serve many nerve cells, or muscle cells. These terminal axonal branchings (L Fig. 22-11) eventually end in structures that are not only specialized and swollen, but are tightly attached to the neurons or muscle cells being innervated. The swellings are synapses, if on nerve cells, motor end-plates (neuromuscular/myoneural junctions), if on skeletal muscle.
c) Enclosing the dendrites, body, axon and synapses of a nerve cell are numerous glial cells, helping set ion levels, remove toxic chemicals, and provide nutrients. Certain glial cells wrap an interrupted fatty sheath of myelin around the axon to make the action potential travel much faster.
d) The soma of the neuron is responsible for maintaining not only its own structures and materials, but the contents and membrane of all the dendrites, the axon, and the synapses - a huge far-flung empire. The complicated molecular materials for the continued upkeep of the neuron are synthesized from small molecules in the cell body, segregated, and transported down either the axon or the dendrites, creating several distinct requirements and mechanisms.
F Plasmalemma or cell membrane
1 There is nothing in our everyday experience of man-made membranes - plastic, latex, leather, etc. - to acquaint us with a membrane that is living, very dynamic, able to assemble and repair itself, and adapt to very many tasks.
2 Such is the importance of the cell membrane that your idea of the plasmalemma will continue to grow throughout medical school and subsequent practice - what you hear this semester is only a seedling, but the eventual fruit will be understanding medicine better (and passing exams).
3 The fundamental requirement for a membrane around, or inside, a cell is a molecule the cell can synthesize, that joins other molecules in a way that excludes water (L Fig. 9-14, p. 255), and in fact divides the water into extracellular (outside) and cytosolic (inside the cell).
4 This lipid-based process achieves a membrane, but it must then be possible for proteins to be inserted into and through the membrane (L Fig 2-9; Fig. 10-4, p. 272, Fig. 10-10, p. 277) for a variety of tasks.
5 Earlier the cell membrane was likened to a skin, because skin is alive, flexible, allows materials to pass through it selectively, and has special structures inserted through it, such as hair follicles. Indeed, a hair follicle functions similarly to a membrane receptor molecule - brushing against the hair causes a movement that is conveyed to under the epidermis, where sensory receptors on the hair follicle pick up the movement, and convert it to an electrical signal. The receptor molecule is bent (as a molecular deformation) by the activating 'ligand' molecule's binding to it. Then through the transmembrane region(s) of the receptor a stimulus passes to the region of the molecule protruding into the cytosol, where the stimulus alters other molecules attached there. This change sets off a cascade of internal signals, eventually causing something useful to be performed by the cell (L Fig. 22-12, p. 749 Fig. 22-25, p. 763, Fig. 22-32, p. 771).
6 How else do these membrane proteins help the cell carry out its tasks? Some general examples.
a) Many cells have to be attached to other cells (L Fig 2-26): cell-cell attachment.
b) Certain of these cell-cell attachments provide intimate communication, so that activities occur in unison in a group of cells: cell-cell communication.
c) In all cells the plasmalemma has to be attached to the internal skeleton of the cell - the cytoskeleton (L Fig. 2-26 ): plasmalemma-cytoskeletal attachment.
d) The cell membrane can be reinforced, where the going is mechanically tough - the surface cells of skin, or chemically unpleasant - the surface of the cells lining the urinary bladder, or cells circulating in the blood: cell protection.
e) Several protein molecules are organized into a channel (L Fig. 10-22, p. 288) that controls the passage of ions through the membrane, thereby establishing an electrochemical gradient.
f) Other proteins work together to assist the entry of nutrients, e.g., glucose, into the cell: facilitated transport (L Fig. 10-17, p. 284).
g) As outlined in G.5 above, membrane receptors allow chemical signals from other cells, close or distant, to bind and to start a chain of messages, reaching deep into the cell to integrate the cell's activities with the needs of the whole organism: signal transduction.
G Unit membrane
1 The cell applies the same principles of construction to making the membranes of the membranous organelles, such as the endoplasmic reticulum, as it does for the plasmalemma, employing back-to-back lipid for the water-repelling or hydrophobic phase. Unit membrane is the term for the generic membrane, which does not actually exist since all membranes are specialized. Three further points need to be made.
2 Membrane constituents are in molecular flux, with turnover.
3 Membranes move from one site and structure to another, thus, from ER to the Golgi complex, from the Golgi to storage vesicles, from storage vesicles to become part of the plasmalemma, and from the plasmalemma back into the interior of the cell as endocytosed vesicles. The traffic in vesicle contents is also a traffic in membrane. ( endocytosis)
4 The membranes enclosing organelles have a complex cytosol on one side, but a simpler mix of materials on their face away from the cytosol and toward the interior of the organelle.
H Nucleus and Nuclear membrane
1 Some of the ideas presented thus far for the cell and cell membrane carry over to the nucleus - major working chemicals, a skeleton, membrane enclosure, but with holes for transport and communication, and renewal.
2 The microscopist's view of the nucleus partly overlaps, but mostly complements that of the biochemist. The visible structures for the histologist are: chromosomes (L Fig. 23-4, p. 795), genes binding tagged DNA probes, chromatin - more or less relaxed chromosomes interacting with a great variety of bound proteins (L p. 806), the nucleolus - ribosomal RNA with attached proteins, the nuclear envelope (L Fig. 2-8 ), and the attached nuclear skeleton of fine thread-like filaments.
3 The purists or sticklers for nomenclature call the nuclear membrane the 'nuclear envelope' (L 2-12), to reinforce the point that there are two unit membranes, with a space in between. This arrangement allows the outer membrane to interact with the cytosol, using its attached ribosomes, while the inner membrane works with the nuclear skeleton and other components inside the nucleus. The doubled membrane probably also makes stronger and more efficient the device of nuclear pores. At regular intervals over the nuclear envelope, there are aggregates of special proteins that create a hole - the actual pore - through which most, if not all, of the traffic takes place. The pore complex includes the pore, the proteins creating the pore, accessory transport proteins, and the adjacent region of the nuclear membranes. The pore traffic between cytosol and nucleoplasm comprises nucleosides, other small molecules, enzymes, signalling molecules, structural proteins, mRNA, etc. (L Fig. 22-39).
J Endoplasmic reticulum is a term referring to what oldtime microscopists saw as a network in the cytoplasm of the cell (endo - within). Unfortunately, there are several different networks, with the only shared element being the use of unit membrane to construct narrow, multiple, branching tubular or flattened enclosures.
1 Endoplasmic reticulum (ER), without further qualification, usually refers to the granular endoplasmic reticulum, named for the ribosomes, attached in a grouped and regular manner to the cytosolic face of the single membrane. The space inside the membrane is the cisterna or cisternal space.
2 Directing protein synthesis is the role of ribosomes (ribo for the ribonucleic acid of the RNAs present). The protein synthesized from some ribosomes (most ribosomes in young, developing cells) passes directly into the cytosol. However, ribosomes attached to the ER send the elongating protein molecule (L Fig. 26-36) through channels in the ER membrane into the cisternal space, isolated from the cytosol, and able to be transported elsewhere or eventually out of the cell.
3 In contrast to the rough or granular ER, the other endoplasmic reticula lack ribosomes and are thus termed smooth ER, but the roles are diverse, depending on the enzymes associated with the membrane:
Roles of smooth ER
1 "You always pay for the lunch, but the radicals are free". Normal metabolism, tissue injury, and defense produce molecules, where some oxygen atoms acquire a very unstable and highly reactive unpaired electron - these free radicals damage lipids, DNA, and other critical molecules of the cell. In the tightly assembled lipid molecules of membranes, the damaged lipid molecule itself becomes a free radical, and passes on the damage to its neighbor as a chain reaction - lipid peroxidation, which weakens and can destroy the plasmalemma or internal cell membranes. One trusts that your lunch includes fruit and veg. with their constituents that can mop up or scavenge the free radicals, before too much damage is done.
2 "Put the grommet in". For wires and vacuum tubing to pass from the engine compartment of your car to the dash in the passenger compartment, the metal firewall has holes in which are inserted plastic or rubber plugs, each with a large central hole. The grommet is protective to stop the wire chafing on a metal edge, not so the open plugs inserted in plasmalemmas. The perforin molecule is deliberately inserted by one cell into the cell membrane of another cell from the outside, in order to make the target cell so leaky that it dies: helpful if this cell has been corrupted by a virus (L 2-27), harmful, if a sound cell is wrongly targetted.
3 " One thing leads to another". A membrane protein can be defective because the gene coding for it is bad, as happens in cystic fibrosis, where a poorly constructed chloride-ion channel in certain cells causes, among other results, the mucus of the airway to be thick and clogging, so that death comes early.
microvilli iiiiiiiii __________________ ! ! zo }J | | | | | | | | | | ENTEROCYTES : : za }C |o|o|o|o|o|o|o|o|o| | | ma }o -------------------------------basal lamina | | \ / \ / \ / } | GC | \/ BV \/ \ / \ } LAMINA | | ma/d / \ / \ BV \ \ } PROPRIA | OO | \ / \ \ \ } | OO | ENTEROCYTE | | ATTACHMENTS -=-=-=-=- ^ ^hd ! zo zonula occludens } junctional : za zonula adherens } complex | ma/d macula adherens } = hd hemi-desmosome
2 The gut epithelial cell:
With the cells thus fastened together side-by-side, similar half-desmosomes hold the basal surface of the cell to the basement membrane.
4 Transport is predominantly in at the top, and out at the base and sides of the cell. As the marshal for transport, the Golgi complex sits high above the nucleus. Digestion creates small molecules from large, so the luminal cell membrane has the appropriate transporters, e.g. for glucose, and pumps. Transport on a bulk or supramolecular scale is achieved by endocytosis.
Steps of endocytosis (L p. 32; Fig. 29-39, p. 678, Fig. 26-43, p. 935) are:
a) attachment of the material to the outside of the cell;
b) attachment of actin filaments (L 2-19) to the cytosolic side of the plasmalemma to provide pull;
c) pulling the membrane down as a bulge into the cell, bringing the target material down with it;
d) pushing the upper part of the bulge into a constricting neck over the target;
e) fusing the membrane of the neck to create a closed internal endocytic vesicle, while cutting the connection of the neck with the plasmalemma, so that the latter is returned to an intact condition.
f) The actin filaments, with their associated molecules, can now take the vesicle off toward other organelles for processing of the vesicle content.
[Running this process in reverse allows material created inside the cell, and stored in vesicles (storage granules), to be extruded from the cell by the process of exocytosis. For example, the enterocyte will export glycoproteins, including some digestive enzymes, to remain as a thick sticky layer - the glycocalyx - just outside the luminal surface, and able to direct the final stages of digestion outside the cell; lipds are packaged for basolateral-release: eventual destination - the blood]
Taken together, the two bulk transport systems of the cell membrane - exocytosis and endocytosis - constitute a kind of quickly set up "revolving-room mechanism".
To greatly increase the surface area for absorption, the apical plasmalemma is thrown up into numerous fingerlike extensions - microvilli: one of several cell-surface specializations.
5 Internal reinforcement of the cell holds its shape, gets the microvilli to protrude, and makes the cell-cell and cell-basement membrane attachments more effective. The thread-like cytoskeletal filaments that accomplish this are: (i) substantial, but relatively inert keratin intermediate filaments (IFs, L p. 45), and (ii) the thin actin filaments for moving vesicles and the cell membrane. Filaments of both classes are throughout the cytoplasm, but are concentrated in the uppermost region as the terminal web, and as bundles inserting into the specialized attachment devices, e.g., desmosomes and hemidesmosomes. Thus, the cell membrane, organelles, and the nucleus are all held together in their correct positions. [Neurofilaments are the neuron's equivalent to keratin IFs in epithelial cells.]
Away from the surface of the cell, microtubules remain responsible for moving vesicles.
Intricate and mobile cellular defenses combat microrganisms penetrating any epithelium and basement membrane, into the underlying connective tissue. The macrophage helps coordinate this defense, and then removes the debris of dead and disintegrating cells, bacteria, damaged connective-tissue fibers, etc. The macrophage can attach to the fibers, but free itself to recognize, move towards and attach to, and eat damaged bodies.
1 Phagocytosis - the target material is ingested by the process of endocytosis, in this instance termed phagocytosis. The intracellular membrane-enclosed phagosome holding the target is then moved by microtubules to be fused with enzyme-containing lysosomes, also membrane-enclosed, for digestion.
2 Lysosomes contain destructive or hydrolytic enzymes (L p.34) for the main categories of biological macromolecules, and some special materials, thus, elastase digests elastic fibers and, incidentally, other structures. The lysosome is built up from vesicles received from the Golgi complex (L 26-39, p. 932), and containing the enzymes originally synthesized in the granular ER. Although the membrane of the lysosome is labile, in fusing with phagosomes and other endocytosed units, it protects the cytosol from the digestion going on inside.
3 The Cytoskeleton has an abundance of actin under the cell membrane in either soluble form, or assembled as filaments. By switching between these forms, as well as having some actin fastened to the plasmalemma (L Fig. 2-18 (a)), the cell is able to send forward extensions and pull along its rear end, so as to move - cell motility, and to enfold material for phagocytosis. Microtubules are still necessary deep in the cell for the vesicle traffic around the ER, Golgi, and lysosomes.
4 Plasmalemmal proteins: Macrophage-specific ones recognize and attach to targets for destruction, and briefly grasp connective-tissue fibers as the macrophage swings through the jungle of fibers.
5 Cytokines are small molecules released by the macrophage to give coordinating orders to other cell types, in particular, cells involved in defense. The names are derived in various ways, e.g., interleukins (IL-1, IL-2, etc.), transforming growth factor beta (TBF-ß). Clinicians now use certain cytokines on patients to improve cell behavior in various diseases.
M Cardiac muscle cell/myocyte
Imagine a ring of octopuses holding tentacles. If they all shorten their tentacles at the same time, while keeping the attachments, the ring gets smaller. Likewise, heart muscle consists of cells tightly attached end-to-end, which can contract (shorten) at much the same time, thereby squeezing blood on to the next heart chamber, or out of the heart: the analogy misleads only in the cardiac myocytes' not extending cell processes. The needs are for the myocytes to contract, to be firmly joined (so that they can pull on each other), and to propagate the stimulus to contract rapidly through the muscle. Unlike skeletal muscle, there is no need for elaborate connective tissue to transmit the force to a site outside the muscle, nor for muscle cells to contract individually to furnish finely graded force.
1 Contraction (shortening) of muscle needs:
a) structures oriented lengthwise in an elongated cell - actin & myosin filaments (L 2-25 (b));
b) certain of the structures to be attached to the cell membrane - myosin filaments;
c) other structures to attach to and move with force along the first (b) - actin filaments along myosin, with the myosin doing the pulling (L Fig. 7-32, p. 191); the actin filaments are anchored less directly to the plasmalemma;
d) a means of supplying immediate energy for the force, on the timescale of force generation - adenosine triphosphate (ATP) (L Fig. 13-12, p. 383);
e) a more distant, general provision of energy - mitochondria;
f) an immediate local trigger for contraction - calcium ion released from sarcoplasmic reticulum
g) coordination of contraction throughout the cell by a prompt, widespread stimulus for the local release of Ca2+ - a sarcolemma/plasmalemma specialized to be (i) an excitable electrical-potential-propagating membrane, (ii) able to reach down locally by transverse (T) tubules into the interior of the cell to the sarcoplasmic reticulum, and (iii) at some place be sensitive to stimulation from adjacent cells - by gap junctions in cardiac muscle, motor endplates for skeletal muscle. ['Myo' and 'sarco' are adjectives for muscle, thus the plasmalemma is the sarcolemma.]
2 Maximizing the force and its usefulness is a mostly cytoskeletal accomplishment in efficiency, thus:
a) The filaments are bundled into longitudinal units - myofibrils, each surrounded by a sheath of sarcoplasmic reticulum and mitochondria (L Fig. 22-7 ).
b) The filaments are set in register, side by side, so that the actin filaments can be anchored along the plane of a Z disc (from its edge-on appearance usually called a Z line), with their other, free, ends inserting partway between the myosin filaments. The myosin filaments are also arranged precisely alongside each other and stabilized by sundry accessory proteins.
_________________ A __________________ | | ____ I ___ ____ I ____ | | | | M N N | |----- | ------------------|--------------------- | |-----------|------------------- | ---------------------|-------------- Relaxed _|----- | ------------------|--------------------- | myofibril |-----------|------------------- | ---------------------|-------------- |----- | | | | |_________| | Z H zone Z <--------------------- Sa ------------------------->
c) This array of thin actin and thick myosin filaments, repeated along the muscle cell or fiber, produces a striated or crossbanded appearance in cardiac and skeletal muscle. The pattern is of a pale I band, bisected by a thin dark Z line (L Fig. 2-25), a dark A band of myosin filaments, with a paler central region where the actin filaments from each direction have failed to reach, then the next I band. The fiber can be viewed as units fastened by Z lines in series, with each unit from one Z line to the next being a sarcomere. Note that an I band includes parts of two sarcomeres.
3 Intercalated disks are the end-to-end cell attachments, taking the place of a Z line, which (i) make a strong mechanical connection by fascia adherentes - structures like epithelial desmosomes, but more extensive, and (ii) connect the myocytes electrically by gap junctions. At gap junctions, the membranes of the two cells get very close but, unlike at a tight or occluding junction, do not fuse. At the same time, proteins run across the gap from cell to cell, providing a channel for current, as ions, to flow. Gap junctions let electrical activity and contraction, started in a few cardiac myocytes, spread rapidly through the muscle of a heart chamber. For both efficient squeezing and the spread of contraction, cardiac muscle cells, unlike skeletal muscle fibers, branch, so that one cell may be fastened to three by three intercalated disks.
4 Cardiomyopathy is a sickness of the cardiac muscle, seen in congestive heart failure, where the ventricle enlarges, but the wall becomes thin and defective. Among the changes are:
a) Disruption of the cytoskeleton, with the intermediate filaments and other proteins not adequately reinforcing the Z lines, and properly spacing and securing the principal cytoskeletal workers - the actin and myosin filaments.
b) A subtle, but nevertheless weakening, shift in the composition of the contractile proteins - actin, myosin, and several accessory ones. This is a damaging molecular change at the level of gene transcription - a return to the expression of fetal isoforms of the molecules, but unlike cystic fibrosis and Duchenne muscular dystrophy, this is not a genetic defect (L Table 6-6, p. 147), but can happen to anyone.
c) An increase in the normally sparse collagen connective-tissue fibers in the wall - a fibrosis, which impedes the already weakened muscle cells. Fibrosis is also a problem in diseased lungs and livers, where again activated macrophages release cytokines which overstimulate fibroblasts to make collagen.
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